(1) Field of the Invention
The present invention lies in the field of biodegradable and nontoxic biological adhesives intended for surgical or therapeutic use.
More precisely, the present invention deals with a biocompatible, bioresorbable and nontoxic adhesive composition based on at least one macromolecular polyaldehyde.
It also relates to such an adhesive composition additionally comprising a collagen-based component.
It also relates to a process for crosslinking solubilized collagen which makes it possible to obtain an adhesive material intended to be applied quickly to tissues and/or a biomaterial.
(2) Description of the Related Art
The crosslinking of collagen can be carried out either by a chemical route, with the aid of tanning agents such as glutaraldehyde or formaldehyde or alternatively diisocyanate or other reactants, or by using physical agents such as gamma, beta or ultraviolet radiations.
However, this last method is cumbersome and sometimes difficult to implement and, besides the crosslinking, it also produces scissions.
Insofar as the chemical route is concerned, treatment with glutaraldehyde (or formaldehyde) is the treatment most frequently employed for crosslinking collagen and consists in immersing powders, films, gels or more or less concentrated solutions of collagen in a solution of glutaraldehyde. It has a certain number of disadvantages, depending on the applications. The introduction of glutaraldehyde into an aqueous collagen-based structure can especially entail a rapid separation of excess glutaraldehyde by diffusion through the gel formed.
In surgery or therapy this gives rise to toxic reactions, resulting in tissue necrosis or less severe reactions, leading to poor or retarded cicatrization. This is the case with the collagen-based adhesive available on the market today.
In this adhesive, called GRF, the crosslinking of gelatin is produced by formaldehyde in the presence of resorcinol, the latter being used essentially to reduce the dissolving of the adhesive mass. This adhesive has been employed between the 1960s and the 1980s, but, in fact, its use in surgery is now restricted to a few rare applications where the benefit exceeds the risks (aortic dissection) because of the possibility of separation of the formaldehyde and because of its toxicity. An excessive quantity of formaldehyde is needed to obtain rapid crosslinking of the collagen-based gel and good adhesion to the surrounding tissues. This excess of formaldehyde is responsible for the poor biocompatibility of the GRF adhesive. It is therefore not possible today to generalize the use of this adhesive to the cicatrization of surgical or chronic wounds, to the protection or the leakproofing of sutures or to the release of medications.
A recent improvement has just been proposed, by increasing the viscosity of the medium which contains the formaldehyde, the glutaraldehyde or other dialdehyde by adding a gelling agent such as agar (G. Izoret patent application, Wo 96/14368). However, this does not eliminate the risk of diffusion of the crosslinking agent, even though the diffusion is slowed down.
Furthermore, the biocompatibility of collagen crosslinked with toxic chemical agents can be improved by reducing the quantity of crosslinking agents employed to a minimum. This is what is done in preformed materials intended to be implanted, where the reaction time can be prolonged as much as necessary by the manufacturer of the material. In this case small quantities of crosslinking agent are employed and the crosslinked material is carefully washed at the end of preparation to remove any excess of reactant.
The final crosslinked material employed by the surgeon is in this case a solid or a suspension of collagen-based fibres, but these materials are devoid of adhesiveness to the surrounding tissues.
The preparation of a biological adhesive often requires the mixing, by the surgeon himself, in contact with the biological tissues to be treated, of two different solutions permitting a rapid crosslinking of the collagen, of the gelatin or of any other reactive macromolecule or molecule.
For example, the adhesive marketed by the Immuno company under the name of "Tissucol" (Tisseel) and then by Behringwerke under the name of "Beriplast" and by Biotransfusion under the name of "Biocol" is known. This is a concentrated solution of fibrinogen (70-140 mg/ml) containing Factor XIII and fibronectin, the polymerization of which is induced by a solution of thrombin (4 to 400 International Units) in an extemporaneous mixture. The fibrinogen subsequently polymerizes to fibrin to reform a coagulum which ensures the adhesion of the tissues brought into contact.
The difficulties and major problems raised by this product and its components are, on the one hand, the absence of complete characterization and reproducibility of the quantity of each of the components of the fibrinogen solution (Factor XIII, fibronectin, aprotinin) and, on the other hand, the difficulty in viral inactivation of such a product with regard to uncoated viruses like Unconventional Transmissible Agents. This has led to a restriction on the possibility of employing such products on a large scale.
Tardy et al. (French patent application No. 9400715) have described a collagen-based biological adhesive which can be prepared by virtue of a kit consisting, for example, of two separate syringes containing, respectively, a solution of collagen (or gelatin) oxidized with sodium periodate and stored at acidic pH in frozen form at a temperature lower than 0.degree. C., preferably of the order of -20.degree. C., and an aqueous alkaline solution. The mixing of the respective contents is ensured by a mixer connected to the two syringes, after the oxidized collagen (or gelatin) gel has been reheated to about 40.degree. C., in order to obtain a biocompatible adhesive whose crosslinking is accomplished in 2 to 3 minutes.
The properties of this adhesive are advantageous in some applications, but the main problem with this technology is the need for a complex cold system for the distribution of this product, which increases its cost and makes it awkward to use in premises not equipped with a deep-freeze.
It has also been proposed to employ reactive polyethylene glycol derivatives to form biological adhesives based on albumin or collagen (Barrows et al. patent No. WO 96 031 59 Al; D. Sierra--Tissue Sealants Meeting La Jolla, 1996). However these reactants are not very stable in water and can require special storage methods. Their optimum activity pH is alkaline, not physiological. Furthermore, the resorption period of these products is very long, longer than 3 to 4 weeks and this, in some applications, is a major disadvantage.
The incontrovertible need to obtain, rapidly and sometimes virtually instantaneously, the solidification of a fluid solution in order to obtain a strong adhesion, can make it necessary to employ an excess of chemical crosslinking reactants, which results in toxicity and in mediocre tissue biocompatibility.
Tissue adhesives based on commercial gelatin and on oxidized starch or glutaraldehyde have also been recently proposed in the document Wo 97/29715 (Fusion Medical Technologies Inc.).
These adhesives form very viscous gels which have to be heated to a high temperature, of the order of 50-80.degree. C., in order to be applied with a syringe.
Besides the risk of potential toxicity depending on the aldehyde used, these adhesives can damage the treated tissues, in particular because of their application temperature.